Enkephalins and endorphins are morphine-like substances which have recently been discovered to be endogenous in various animal species, including mammals and man, and serve as the body's natural pain relievers. Enkephalins and endorphins are peptides and/or polypeptides. Enkephalins are normally present in the brain.
It has heretofore been observed that enkephalins and endorphins have an ability to act as analgesics to abolish pain when administered to various animals by certain special routes (e.g. directly into the brain) which pose practical drawbacks to useful administration. Further, these substances have a serious drawback in that they are addicting, and tolerance develops to them. In addition, they have an effect of very short duration of action when administered to mammalian hosts, due to their rapid destruction by other substances endogenous to animal species, including mammals and man. These endogenous substances that destroy the action of enkephalins were originally believed to include at least two known enzymes, carboxypeptidase A and leucine aminopeptidase. It was since learned, however, that carboxypeptidase A is not involved in the destruction of the enkephalins and endorphins.
Regardless of the endogenous substances responsible for the destruction of enkephalin when isolated or synthesized and administered to mammals, in an attempt to overcome the problem, various derivatives of enkephalin, the endorphins and other beta-lipotropin fragments 61-91 were synthesized, and reported in the literature. Based on earlier successful attempts by Coy and Schally to block enzymatic degradation upon administration of LHRH leutinizing hormone by replacing a naturally occuring amino acid in the naturally occuring peptide sequence with a D-amino acid, D-alanine, and other D-amino acids including D-leucine and D-phenlylanine, were introduced into the amino acid sequence of enkephalin and other beta-lipotroprin fragments 61-91 in place of the naturally occuring glycine in the 2-position, or other naturally occuring L-amino acids in the naturally occuring amino acid sequence. Other modifications were investigated, but none of these derivatives have met with commercial success despite the concerted efforts of investigators at a number of major pharmaceutical companies, universities and government agencies. None of these derivatives have met with commercial success, and the treatment of moderate to severe acute and chronic pain still requires administration of potent analgesic agents such as codeine, propoxyphene, demerol, morphine and the like.
Thus, a need remains for analgesic agents which provide relief from acute or chronic moderate to severe pain which can not be treated with aspirin, aspirin-like non-steroidal anti-inflammatory agents and acetominophen. The present invention fulfills the long-standing need for safe, effective analgesic agents which can be used in in the treatment of moderate to severe, acute or chronic pain.
D-phenylalanine, DL-phenylalanine, D-leucine and hydrocinnamic acid are known chemicals listed in the Merck Index.
Use of D-phenylalanine has been reported from the Faculty of Medicine, Buenos Aires, Argentina in Therapy of Depression by Phenylalanine" Arzneim Forsch, Vol. 25, NR1 (1975), and "Use of D-Phenylalanine in Parkinson's Disease", Arneim Forsch, Vol. 26, NR4 (1976). In the report of treatment of depression, DL-phenylalanine was administered in quantities of 50 to 100 mg per day for 15 days, and D-phenylalanine was administered in the amount of 100 mg per day for 15 days.
A commercial drug, sold under the Trademark "Deprenon", is available for treatment of depression by oral ingestion of 3-4 capsules per day. Deprenon's specifications states that each capsule contains:
D-Phenylalanine: 50 mg PA0 Mannitol: 90 mg PA0 Pervidone: 4 mg PA0 Magesium stearate: 3 mg.
Leucine and phenylalanine are also known to be useful as nutrients.